In adults, bone remodeling involves (1) destruction of fatigued or microdamaged bone with the release of Ca++, Pi, and hydrolyzed fragments of bone matrix into blood and (2) synthesis of osteoid (yet to be mineralized bone matrix) at the site of resorption, followed by controlled mineralization of the osteoid by Ca++ and Pi to form new bone. Bone remodeling occurs continually at about 2 million discrete sites throughout the skeleton by packets of bone cells referred to as the basic multicellular units (BMU).
The cells involved in bone remodeling fall into two major classes: cells that form bone (osteoblasts) and cells that destroy or resorb bone (osteoclasts). The process of bone remodeling is a highly integrated process (
Fig. 40.9 ). Osteoblast-lineage cells express factors that induce differentiation of osteoclasts from progenitors of the monocyte/ macrophage lineage and also promote mature osteoclast function. Osteoblasts release monocyte colony-stimulating factor (M-CSF), which expands and differentiates early hematopoietic progenitors (CFU-GM) into preosteoclasts that express a cell surface receptor called RANK (receptor •Fig. 40.9 Osteoblastregulationofosteoclastdifferentiationandfunction.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) activator of nuclear factor [NF]-κB). Osteoblast-lineage cells display RANK ligand (RANKL) on their cell surface. RANKL then binds to RANK on preosteoclasts and induces osteoclastogenesis. This process involves fusion of several osteoclast precursors, giving rise to a large multinucleated osteoclast. The perimeter of the osteoclast membrane facing mineralized bone adheres tightly to the bone and seals off the area of osteoclast-bone contact (see
Fig. 40.9 ). The region within the sealed zone forms a highly invaginated membrane called the ruffled border, from which HCl and hydrolytic lysosomal enzymes are secreted. The acidic enzyme-rich microenvironment beneath the osteoclast dissolves the bone mineral, thereby releasing Ca++ and Pi into blood, and also degrades the bone matrix. There is an additional inhibitory component of the RANK/RANKL system. Osteoblast-lineage cells can also produce a soluble factor called osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and inhibits osteoclast differentiation and function (see
Fig. 40.9 ). Therefore the balance between RANKL and OPG expression by osteoblasts determines how much osteoclast differentiation and bone resorption will occur.
Following bone resorption in the BMU, there is a brief reversal phase, then adjacent osteoblasts migrate into the resorbed area and begin to lay down osteoid. Several components within osteoid (pyrophosphate, alkaline phosphatase, specific glycoproteins) promote slow, controlled mineralization, a process that removes Ca++ and Pi from blood. As the osteoblasts become surrounded by and entrapped within bone, they become osteocytes that sit within small spaces called lacunae. Osteocytes remain interconnected through cell processes that run within canaliculi and form communicating junctions with adjacent cell processes. The new concentric layers of bone, along with the interconnected osteocytes and the central canal, are referred to collectively as a Haversian system or osteon. Emerging evidence indicates that osteocytes are able to sense mechanical stress in bone and signal that additional local bone formation is needed. They can also detect microdamage in bone that serves to initiate remodeling at that location.